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Martino, M.;  Naso, V.;  Loteta, B.;  Canale, F.A.;  Pugliese, M.;  Alati, C.;  Musuraca, G.;  Nappi, D.;  Gaimari, A.;  Nicolini, F.; et al. Chimeric Antigen Receptor T-Cell Therapy. Encyclopedia. Available online: (accessed on 09 December 2023).
Martino M,  Naso V,  Loteta B,  Canale FA,  Pugliese M,  Alati C, et al. Chimeric Antigen Receptor T-Cell Therapy. Encyclopedia. Available at: Accessed December 09, 2023.
Martino, Massimo, Virginia Naso, Barbara Loteta, Filippo Antonio Canale, Marta Pugliese, Caterina Alati, Gerardo Musuraca, Davide Nappi, Anna Gaimari, Fabio Nicolini, et al. "Chimeric Antigen Receptor T-Cell Therapy" Encyclopedia, (accessed December 09, 2023).
Martino, M.,  Naso, V.,  Loteta, B.,  Canale, F.A.,  Pugliese, M.,  Alati, C.,  Musuraca, G.,  Nappi, D.,  Gaimari, A.,  Nicolini, F.,  Mazza, M.,  Bravaccini, S.,  Derudas, D.,  Martinelli, G., & Cerchione, C.(2022, November 22). Chimeric Antigen Receptor T-Cell Therapy. In Encyclopedia.
Martino, Massimo, et al. "Chimeric Antigen Receptor T-Cell Therapy." Encyclopedia. Web. 22 November, 2022.
Chimeric Antigen Receptor T-Cell Therapy

The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective CAR-T. Chimeric antigen receptor T-cell therapy (CAR-T) is a type of immunotherapy in which a patient’s T cells are collected and genetically engineered to improve their ability to recognize and kill cancer cells. However, several issues are still unsolved and represent the challenges for the coming years. The lack of initial responses and early relapse are some hurdles to be tackled. Moreover, new strategies are needed to increase the safety profile or shorten the manufacturing process during CAR-T cells therapy production. Finally, the clinical experience with CAR-T cells for solid tumors has been less encouraging, and development in this setting is desirable.

CAR-T manufacturing toxicities

1. Introduction

Chimeric antigen receptor T-cell therapy (CAR-T) is a type of immunotherapy in which a patient’s T cells, immune cells with anti-cancer activity, are collected and genetically engineered to improve their tropism and promote the elimination of cancer cells [1][2][3][4]. The modified cells are expanded in the laboratory and then returned to the patient to fight cancer. The year 2018 represents a milestone in the history of medicine: the Food and Drug Administration (FDA) [5][6] and the European Medicines Agency (EMA) [7] approved the first two products containing autologous T cells genetically modified ex vivo, tisagenlecleucel and axicabtageneciloleucel, for commercial use, revolutionizing the treatment landscape for relapsed or refractory (R/R) ALL and R/R non-Hodgkin lymphoma (NHL). However, history goes on, and in the last year, the FDA approved lisocabtagenemaraleucel in R/R NHL [8] and idecabtagenevicleucel in R/R multiple myeloma (MM) [9][10][11]. In addition, brexucabtageneautoleucel has been approved for treating adult patients with R/R mantle cell lymphoma [12] and is now being studied in patients with R/R B-ALL [13]. Moreover, the rolling submission of a biologics license application has been completed to support the approval of the investigational ciltacabtageneautoleucel in R/R MM [14]. Researchers also published data about an autologous CAR-T that uses a novel binding domain to target a B-cell maturation antigen (CARTddBCMA) in R/R MM, designed to reduce the risk of immunogenicity, while increasing stability [15]. The main characteristics of the constructs and the clinical indications are summarized in Table 1.
Table 1. Main characteristics of the CAR-T constructs and clinical indications.


  1. Kamb, A.; Go, W.Y. Cancer T-cell therapy: Building the foundation for a cure. F1000Research 2020, 9, 1295.
  2. Martino, M.; Alati, C.; Canale, F.; Musuraca, G.; Martinelli, G.; Cerchione, C. A Review of Clinical Outcomes of CAR T-Cell Therapies forB-Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2021, 22, 2150.
  3. Martino, M.; Canale, F.A.; Alati, C.; Vincelli, I.D.; Moscato, T.; Porto, G.; Loteta, B.; Naso, V.; Mazza, M.; Nicolini, F.; et al. CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma. Cancers 2021, 13, 2639.
  4. Schepisi, G.; Cursano, M.C.; Casadei, C.; Menna, C.; Altavilla, A.; Lolli, C.; Cerchione, C.; Paganelli, G.; Santini, D.; Tonini, G.; et al. CAR-T cell therapy: A potential new strategy against prostate cancer. J. Immunother. Cancer 2019, 7, 258.
  5. FDA Approves Tisagenlecleucel for Adults with Relapsed or Refractory Large B-Cell Lymphoma. Available online: (accessed on 5 March 2018).
  6. FDA Approves Axicabtagene Ciloleucel for Large B-Cell Lymphoma. Available online: (accessed on 9 August 2022).
  7. First Two CAR-T Cell Medicines Recommended for Approval in the European Union. Available online: (accessed on 9 August 2022).
  8. FDA Approves Lisocabtagene Maraleucel for Relapsed or Refractory Large B-Cell Lymphoma. Available online: (accessed on 9 August 2022).
  9. FDA Approves Idecabtagene Vicleucel for Multiple Myeloma. Available online: (accessed on 9 August 2022).
  10. Chen, Y.; Nagarajan, C.; Tan, M.S.; Martinelli, G.; Cerchione, C. BCMA-targeting approaches for treatment of multiple myeloma. Panminerva Medica 2021, 63, 28–36.
  11. Juan, M. CAR T cells targeting options in the fight against multiple myeloma. Panminerva Medica 2021, 63, 37–45.
  12. FDA Approves Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma. Available online: (accessed on 9 August 2022).
  13. Shah, B.D.; Ghobadi, A.; Oluwole, O.O.; Logan, A.; Boissel, N.; Cassaday, R.D.; Forcade, E.; Bishop, M.R.; Topp, M.S.; Tzachanis, D.; et al. Phase 2 results of the ZUMA-3 study evaluating KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). J. Clin. Oncol. 2021, 39, 7002.
  14. Berdeja, J.G.; Madduri, D.; Usmani, S.Z.; Jakubowiak, A.; Agha, M.; Cohen, A.D.; Stewart, A.K.; Hari, P.; Htut, M.; Lesokhin, A.; et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet 2021, 398, 314–324.
  15. Frigault, M.J.; O’Donnell, E.; Raje, N.S.; Cook, D.; Yee, A.; Rosenblatt, J.; Gibson, C.; Logan, E.; Avigan, D.; Bishop, M.R.; et al. Phase 1 Study of CART-ddBCMA, a CAR-T therapy utilizing a novel synthetic binding domain, for the treatment of subjects with relapsed and refractory multiple myeloma. J. Clin. Oncol. 2021, 39, 8015.
  16. Shah, N.N.; Johnson, B.D.; Schneider, D.; Zhu, F.; Szabo, A.; Keever-Taylor, C.A.; Krueger, W.; Worden, A.A.; Kadan, M.J.; Yim, S.; et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: A phase 1 dose escalation and expansion trial. Nat. Med. 2020, 26, 1569–1575.
  17. Yan, L.; Qu, S.; Shang, J.; Shi, X.; Kang, L.; Xu, N.; Zhu, M.; Zhou, J.; Jin, S.; Yao, W.; et al. Sequential CD19 and BCMA-specific CAR T-cell treatment elicits sustained remission of relapsed and/or refractory myeloma. Cancer Med. 2020, 10, 563–574.
  18. Killock, D. Anti-CD22 CAR T cells in ALL. Nat. Rev. Clin. Oncol. 2020, 17, 391.
  19. Baird, J.H.; Frank, M.J.; Craig, J.; Patel, S.; Spiegel, J.Y.; Sahaf, B.; Oak, J.S.; Younes, S.F.; Ozawa, M.G.; Yang, E.; et al. CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR–refractory large B-cell lymphoma. Blood 2021, 137, 2321–2325.
  20. Zhao, Y.-L.; Liu, D.-Y.; Sun, R.-J.; Zhang, J.-P.; Zhou, J.-R.; Wei, Z.-J.; Xiong, M.; Cao, X.-Y.; Lu, Y.; Yang, J.-F.; et al. Integrating CAR T-Cell Therapy and Transplantation: Comparisons of Safety and Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation After CAR T-Cell or Chemotherapy-Based Complete Remission in B-Cell Acute Lymphoblastic Leukemia. Front. Immunol. 2021, 12, 605766.
  21. Zhang, M.; Huang, H. How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia? Front. Immunol. 2020, 11, 611710.
  22. Jacoby, E. The role of allogeneic HSCT after CAR T cells for acute lymphoblastic leukemia. Bone Marrow Transplant. 2019, 54, 810–814.
  23. Lu, P.; Lu, X.-A.; Zhang, X.; Xiong, M.; Zhang, J.; Zhou, X.; Qi, F.; Yang, J.; He, T. Which is better in CD19 CAR-T treatment of r/r B-ALL, CD28 or 4-1BB? A parallel trial under the same manufacturing process. J. Clin. Oncol. 2018, 36, 3041.
  24. DeAngelo, D.; Ghobadi, A.; Park, J.; Dinner, S.; Mannis, G.; Lunning, M.; Khaled, S.; Fathi, A.; Gojo, I.; Wang, E.; et al. Clinical outcomes for the phase 2, single-arm, multicenter trial of JCAR015 in adult B-ALL (ROCKET study). J. Immunother. Cancer 2017, 5 (Suppl. S2).
  25. Nasta, S.D.; Hughes, M.E.; Namoglu, E.C.; Landsburg, D.J.; Chong, E.A.; Barta, S.K.; Frey, N.V.; Gerson, J.N.; Maity, A.; Plastaras, J.; et al. A Characterization of Bridging Therapies Leading up to Commercial CAR T-Cell Therapy. Blood 2019, 134, 4108.
  26. Lee, D.W.; Santomasso, B.D.; Locke, F.L.; Ghobadi, A.; Turtle, C.J.; Brudno, J.N.; Maus, M.V.; Park, J.H.; Mead, E.; Pavletic, S.; et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. 2019, 25, 625–638.
  27. Siegler, E.L.; Kenderian, S.S. Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights into Mechanisms and Novel Therapies. Front. Immunol. 2020, 11, 1973.
  28. Hong, R.; Hu, Y.; Huang, H. Biomarkers for Chimeric Antigen Receptor T Cell Therapy in Acute Lymphoblastic Leukemia: Prospects for Personalized Management and Prognostic Prediction. Front. Immunol. 2021, 12, 627764.
  29. Banerjee, R.; Marsal, J.; Huang, C.-Y.; Lo, M.; Kambhampati, S.; Kennedy, V.E.; Arora, S.; Wolf, J.L.; Martin, T.G.; Wong, S.W.; et al. Early Time-to-Tocilizumab after B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy in Myeloma. Transplant. Cell. Ther. 2021, 27, 477.e1–477.e7.
  30. Munugala, N.; Dashkevych, U.; Husnain, M. Role of anakinra in the management of icans after CAR T-cell therapy for lymphoma. J. Clin. Oncol. 2022, 40, e19506.
  31. Eyquem, J.; Mansilla-Soto, J.; Giavridis, T.; van der Stegen, S.J.C.; Hamieh, M.; Cunanan, K.M.; Odak, A.; Gönen, M.; Sadelain, M. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 2017, 543, 113–117.
  32. Sachdeva, M.; Duchateau, P.; Depil, S.; Poirot, L.; Valton, J. Granulocyte–macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators. J. Biol. Chem. 2019, 294, 5430–5437.
  33. Ramos, C.A.; Savoldo, B.; Torrano, V.; Ballard, B.; Zhang, H.; Dakhova, O.; Liu, E.; Carrum, G.; Kamble, R.T.; Gee, A.P.; et al. Clinical responses with T lymphocytes targeting malignancy-associated k light chains. J. Clin. Investig. 2016, 126, 2588–2596.
  34. Kim, M.Y.; Yu, K.-R.; Kenderian, S.S.; Ruella, M.; Chen, S.; Shin, T.-H.; Aljanahi, A.A.; Schreeder, D.; Klichinsky, M.; Shestova, O.; et al. Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. Cell 2018, 173, 1439–1453.e19.
  35. Yang, J.; He, J.; Zhang, X.; Wang, Z.; Zhang, Y.; Cai, S.; Sun, Z.; Ye, X.; He, Y.; Shen, L.; et al. A Feasibility and Safety Study of a New CD19-Directed Fast CAR-T Therapy for Refractory and Relapsed B Cell Acute Lymphoblastic Leukemia. Blood 2019, 134 (Suppl. S1), 825.
  36. Jackson, Z.; Roe, A.; Sharma, A.A.; Lopes, F.B.T.P.; Talla, A.; Kleinsorge-Block, S.; Zamborsky, K.; Schiavone, J.; Manjappa, S.; Schauner, R.; et al. Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-hodgkin Lymphoma. Front. Immunol. 2020, 11, 1941.
  37. Benjamin, R.; Graham, C.; Yallop, D.; Jozwik, A.; Mirci-Danicar, O.C.; Lucchini, G.; Pinner, D.; Jain, N.; Kantarjian, H.; Boissel, N.; et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: Results of two phase 1 studies. Lancet 2020, 396, 1885–1894.
  38. Townsend, M.H.; Bennion, K.; Robison, R.A.; O’Neill, K.L. Paving the way towards universal treatment with allogenic T cells. Immunol. Res. 2020, 68, 63–70.
  39. Qasim, W. Allogeneic CAR T cell therapies for leukemia. Am. J. Hematol. 2019, 94, S50–S54.
  40. Poirot, L.; Philip, B.; Schiffer-Mannioui, C.; Le Clerre, D.; Chion-Sotinel, I.; Derniame, S.; Potrel, P.; Bas, C.; Lemaire, L.; Galetto, R.; et al. Multiplex Genome-Edited T-cell Manufacturing Platform for “Off-the-Shelf” Adoptive T-cell Immunotherapies. Cancer Res. 2015, 75, 3853–3864.
  41. Wagner, J.; Wickman, E.; DeRenzo, C.; Gottschalk, S. CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality? Mol. Ther. 2020, 28, 2320–2339.
  42. 63. Marofi, F.; Motavalli, R.; Safonov, V.A.; Thangavelu, L.; Yumashev, A.V.; Alexander, M.; Shomali, N.; Chartrand, M.S.; Pathak, Y.; Jarahian, M.; et al. CAR T cells in solid tumors: Challenges and opportunities. Stem Cell Res. Ther. 2021, 12, 81.
  43. Hanahan, D.; Coussens, L.M. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 2012, 21, 309–322.
  44. Nishio, N.; Diaconu, I.; Liu, H.; Cerullo, V.; Caruana, I.; Hoyos, V.; Bouchier-Hayes, L.; Savoldo, B.; Dotti, G. Armed Oncolytic Virus Enhances Immune Functions of Chimeric Antigen Receptor–Modified T Cells in Solid Tumors. Cancer Res. 2014, 74, 5195–5205.
  45. Mc Granahan, N.; Swanton, C. Clonal heterogeneity and tumor evolution: Past, present, and the future. Cell 2017, 168, 613–662
  46. Finotello, F.; Trajanoski, Z. Quantifying tumor-infiltrating immune cells from transcriptomics data. Cancer Immunol. Immu-nother. 2018, 67, 1031–1040
  47. Li, T.; Fu, J.; Zeng, Z.; Cohen, D.; Li, J.; Chen, Q.; Li, B.; Liu, X.S. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nu-cleic Acids Res. 2020, 48, W509–W514.
  48. Mistichelli, J. Diagnosis Related Groups (DRGs) and the Prospective Payment System: Forecasting Social Implications; Georgetown University: Washington, DC, USA, 1984.
  49. Fetter, R.B.; Freeman, J.L. Diagnosis-related groups: Product line management within hospitals. Acad. Manag. Rev. 1986, 11, 41–54.
  50. Martino, M.; Console, G.; Russo, L.; Meliado’, A.; Meliambro, N.; Moscato, T.; Irrera, G.; Messina, G.; Pontari, A.; Morabito, F. Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: An Activity-based Costing Analysis, Comparing a Total Inpatient Model Versus an Early Discharge Model. Clin. Lymphoma Myeloma Leuk. 2017, 17, 506–512.
  51. Cooper, R.; Kaplan, R.S. The promise--and peril--of integrated cost systems. Harv. Bus. Rev. 1998, 76, 109–119.
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